02 Coeliac Disease
02 Coeliac Disease
02 Coeliac Disease
Coeliac disease
Recognition and assessment of coeliac
disease
Ordering information
You can download the following documents from www.nice.org.uk/CG86
• The full guideline (this document) – all the recommendations, details of how
they were developed, and reviews of the evidence they were based on.
• A quick reference guide – a summary of the recommendations for
healthcare professionals.
• ‘Understanding NICE guidance’ – a summary for patients and carers.
NICE clinical guidelines are recommendations about the treatment and care of
people with specific diseases and conditions in the NHS in England and
Wales.
This guidance represents the view of NICE, which was arrived at after careful
consideration of the evidence available. Healthcare professionals are
expected to take it fully into account when exercising their clinical judgement.
However, the guidance does not override the individual responsibility of
healthcare professionals to make decisions appropriate to the circumstances
of the individual patient, in consultation with the patient and/or guardian or
carer, and informed by the summary of product characteristics of any drugs
they are considering.
Disclaimer ....................................................................................................... 4
Foreword ........................................................................................................ 5
Patient-centred care ...................................................................................... 7
1 Summary .................................................................................................. 9
1.1 Recommendations ............................................................................. 9
1.2 Care pathway .................................................................................. 14
1.3 Overview.......................................................................................... 18
2 Evidence review .................................................................................... 20
2.1 Introduction ...................................................................................... 20
2.2 Prevalence of coeliac disease ......................................................... 21
2.3 The possible long-term consequences of undiagnosed coeliac
disease ........................................................................................... 23
2.4 Signs and symptoms of coeliac disease and coexisting conditions
with coeliac disease ......................................................................... 26
2.5 Serological tests in the diagnostic process for coeliac disease ....... 37
2.6 Research recommendations ............................................................ 59
3 References, glossary and abbreviations ............................................. 61
3.1 References ...................................................................................... 61
3.2 Glossary .......................................................................................... 71
3.3 Abbreviations ................................................................................... 74
4 Methods.................................................................................................. 74
4.1 Aim and scope of the guideline ........................................................ 74
4.2 Development methods ..................................................................... 74
5 Contributors........................................................................................... 79
5.1 The Guideline Development Group ................................................. 79
5.2 Declarations ..................................................................................... 86
This guidance represents the view of NICE, which was arrived at after careful
consideration of the evidence available. Healthcare professionals are
expected to take it fully into account when exercising their clinical judgement.
However, the guidance does not override the individual responsibility of
healthcare professionals to make decisions appropriate to the circumstances
of the individual patient, in consultation with the patient and/or guardian or
carer, and informed by the summary of product characteristics of any drugs
they are considering.
Because coeliac disease can be very effectively treated with a gluten-free diet
it is important to identify people with the undiagnosed disease so as to provide
satisfactory individual treatment and also to improve the overall health of the
community.
The guideline gives recommendations about the clinical signs, symptoms and
types of presentation or conditions that should alert practitioners to consider
the presence of coeliac disease, and suggests a scheme of investigation to
follow when making the diagnosis. It is expected that implementation of the
guideline recommendations will lead to many new cases being diagnosed and
much ill health being alleviated.
This diagnostic process should take into account patients’ needs and
preferences. People with symptoms and/or signs suggestive of coeliac
disease should have the opportunity to make informed decisions, in
partnership with their healthcare professionals. If patients do not have the
capacity to make decisions, healthcare professionals should follow the
Department of Health (2001) guidelines – ‘Reference guide to consent for
examination or treatment’ (available from www.dh.gov.uk). Healthcare
professionals should also follow a code of practice accompanying the Mental
Capacity Act (summary available from www.publicguardian.gov.uk).
If the patient agrees, families and carers should have the opportunity to be
involved in decisions about diagnosis, treatment and care.
Families and carers should also be given the information and support they
need.
1.1 Recommendations
When to offer testing
1.1.1 Offer serological testing for coeliac disease to children and adults
with any of the following signs and symptoms:
1.1.2 Offer serological testing for coeliac disease to children and adults
with:
• Addison's disease
• amenorrhoea
• aphthous stomatitis (mouth ulcers)
• autoimmune liver conditions
• autoimmune myocarditis
• chronic thrombocytopenia purpura
• dental enamel defects
• depression or bipolar disorder
• Down’s syndrome
• epilepsy
• low-trauma fracture
• lymphoma
• metabolic bone disease (such as rickets or osteomalacia)
• microscopic colitis
• persistent or unexplained constipation
• persistently raised liver enzymes with unknown cause
• polyneuropathy
• recurrent miscarriage
• reduced bone mineral density
• sarcoidosis
• Sjögren's syndrome
• Turner syndrome
• unexplained alopecia
• unexplained subfertility.
1.1.5 Inform people (and their parents or carers, as appropriate) that any
testing for coeliac disease is accurate only if the person continues
1.1.6 Inform people that they should not start a gluten-free diet until
diagnosis is confirmed by intestinal biopsy, even if a self-test or
other serological test is positive.
1.1.7 Inform people that when they are following a normal diet
(containing gluten) they should eat some gluten (for example,
bread, chapattis, pasta, biscuits, or cakes) in more than one meal
every day for a minimum of 6 weeks before testing; however, it is
not possible to say exactly how much gluten they should eat.
1.1.10 Before seeking consent to take blood for serological tests, explain:
Serological tests
1.1.12 All tests should be undertaken in laboratories with clinical pathology
accreditation (CPA).
1.1.16 Do not use human leukocyte antigen (HLA) DQ2/DQ8 testing in the
initial diagnosis of coeliac disease. (However, its high negative
1
Investigation for IgA deficiency should be done if the laboratory detects a low or very low
optical density on IgA tTGA test or low background on IgA EMA test.
1.1.18 If serology tests are negative but coeliac disease is still clinically
suspected, offer referral to a gastrointestinal specialist for further
assessment.
Yes
Inform people (and their parents or carers as appropriate) • Inform people who are considering, or who have undertaken, self-testing for
that: coeliac disease that any result from self-testing needs to be discussed with a
healthcare professional and confirmed by laboratory-based tests.
• testing (serology and biopsy if required) is accurate
only if they follow a gluten-containing diet • Before seeking consent to take blood for serological tests, explain:
• when following a gluten-containing diet they should eat – what coeliac disease is
some gluten in more than one meal every day for at
least 6 weeks before testing – that serological tests do not diagnose coeliac disease, but indicate whether
further testing is needed
• they should not start a gluten-free diet until diagnosis is
confirmed by intestinal biopsy (even if a self-test or – the implications of a positive test (including referral for intestinal biopsy and
other serological test is positive) implications for other family members)
• Use serological testing for IgA tissue Check for IgA Negative result
transglutaminase (tTGA) as a first-choice test Negative
result deficiencya but continuing
• Use IgA endomysial antibodies (EMA) testing if clinical suspicion
the result of the tTGA test is equivocal
Positive Negative
result result, no
further
reason to
suspect
coeliac
Offer IgG tTGA tests disease
Positive result and/or IgG EMA tests
a
Investigation for IgA deficiency should be done if the laboratory
detects a low or very low optical density on IgA tTGA test or low
background on IgA EMA test.
Signs, symptoms and conditions associated with coeliac disease
Box A. Offer serological testing to children and adults with any of the
following signs, symptoms and conditions
Signs and symptoms Conditions
• Chronic or intermittent diarrhoea • Autoimmune thyroid disease
• Failure to thrive or faltering growth (in • Dermatitis herpetiformis
children) • Irritable bowel syndrome
• Persistent or unexplained gastrointestinal • Type 1 diabetes
symptoms including nausea and vomiting
• First-degree relatives (parents, siblings or
• Prolonged fatigue (‘tired all the time’) children) with coeliac disease
• Recurrent abdominal pain, cramping or
distension
• Sudden or unexpected weight loss
• Unexplained iron-deficiency anaemia, or
other unspecified anaemia
Coeliac disease can be diagnosed at any age (after the introduction of gluten-
containing foods to the infant weaning diet), and presents in both children and
adults.
Because of the disparate nature of its signs and symptoms, and the historical
belief that it is not a common disease, there is concern that coeliac disease
often goes unrecognised and consequently is underdiagnosed. As a result,
people may present to primary and secondary care on many occasions and
with a range of symptoms before diagnosis. Delayed diagnosis is a concern
because the symptoms of coeliac disease remain untreated and because of
the possible long-term effects of undiagnosed coeliac disease.
There is also some uncertainty about which of the serological tests are most
suitable for use in the diagnostic process for coeliac disease. Small intestinal
biopsy is used as the reference standard for the diagnosis of coeliac disease.
This short clinical guideline aims to improve the care of children and adults
with undiagnosed coeliac disease by making evidence-based
recommendations about its recognition, and about using serological testing to
direct referral for definitive diagnosis by intestinal biopsy.
2 Evidence review
2.1 Introduction
The clinical-effectiveness and cost-effectiveness evidence that was used in
the development of this guideline is summarised in this section. Further details
about the cost-effectiveness evidence, including details of the economic
model, are given in appendix 6.5; details about the clinical evidence are given
in the tables in appendix 6.6.
A search was carried out to identify large population-based studies giving data
on the prevalence of coeliac disease; these are reviewed below.
The AHRQ report (2004) also included studies on the prevalence of coeliac
disease in both children and adults in whom coeliac disease was suspected.
These studies were mainly situated in referral centres and the prevalence of
coeliac disease varied widely: in children it was 1.1 to 4.0% with EMA
serology, 4.6 to 17.0% with biopsy; in adults it was 1.5% with EMA serology,
11.6 to 50.0% with biopsy.
Three additional studies were included (Fraser et al. 2006; Biagi et al. 2008;
Szaflaraka-Sczepanik et al. 2001). These reported a prevalence of coeliac
disease in first-degree relatives of 2 to 17.7%. The study by Fraser et al. was
in the UK and reported a prevalence of 5.5%.
Pregnancy outcomes
An Italian study of 5055 women admitted to obstetric and gynaecological
wards (Greco et al. 2004) identified no pregnancy outcomes for which there
was a significant difference between women with and without coeliac disease.
Outcomes included risk of spontaneous abortion, premature delivery, low birth
weight and intrauterine growth retardation (IUGR).
Fracture risk
A second Swedish study using the national inpatient register (Ludvigsson et
al. 2007) considered hip fractures (14,187 in patients with coeliac disease;
68,852 in patients without coeliac disease) and any fractures (13,724 in
patients with coeliac disease; 65,627 in patients without coeliac disease). The
estimated association of coeliac disease and prior fractures showed an
increased risk of diagnosis with coeliac disease after hip fracture (OR 2.0,
95% CI 1.6 to 2.5, p < 0.001) and after any fracture (OR 1.6, 95% CI 1.5 to
1.8, p < 0.001). This study also identified significantly higher rates of hip
fractures in people with undiagnosed coeliac disease compared with those
with diagnosed coeliac disease. This increased risk was seen throughout the
time period from 10 years to 0.01 years before diagnosis of coeliac disease.
Malignancy
A US study considered the standardised mortality ratio (SMR) of observed to
expected rates for cancers that were diagnosed before or simultaneously with
coeliac disease diagnosis (Green et al. 2003). Although numbers were small,
this study identified significant SMRs for non-Hodgkin’s lymphoma (4
observed cases compared with 0.7 expected, SMR 5.3, 95% CI 2.3 to 13,
p < 0.001), small bowel cancer (3 vs. 0.1, SMR 45, 95% CI 34 to 61,
p < 0.001), oesophageal cancer (3 vs. 0.2, SMR 16, 95% CI 9.7 to 26,
p < 0.001) and melanoma (4 vs. 0.8, SMR 5, 95% CI 2.1 to 12, p < 0.001). It
did not identify a significant difference SMR for colon cancer, breast cancer
and total cancers.
• The GDG agreed the need to include information about the risk of long-
term complications of undiagnosed coeliac disease. It noted that although
there is an increased risk of the specific cancers with undiagnosed coeliac
disease, the overall risk of developing these cancers is low.
• The GDG discussed the different possible long-term effects in children and
adults and agreed an additional recommendation for children specifying
growth failure, delayed puberty and dental complications.
The AHRQ report considered the prevalence of coeliac disease in adults with
iron-deficiency anaemia and in adults with low bone-mineral density. Eight
studies from the AHRQ report with 50 or more participants were included;
these were all in adults with biopsy-proven coeliac disease. The prevalence of
coeliac disease in people with iron-deficiency anaemia ranged from 2.3 to
15%. Four studies from the AHRQ report considered people with low bone
mineral density; these studies identified a prevalence of coeliac disease
ranging from 0 to 3%.
Some people presenting with the features of coeliac disease in the studies
summarised in table 1 had a coexisting condition at the point of diagnosis of
coeliac disease:
Type 1 diabetes
The AHRQ report included papers on the prevalence of coeliac disease in
people with type 1 diabetes; 21 of these studies (people with coeliac disease
proven by biopsy; each had 50 or more participants) were included here.
These studies identified a prevalence of coeliac disease in people with type 1
diabetes of 1.4 to 8.2% in children, 0.3 to 11.3% in adults and 1.7 to 5.7% in
combined child and adult studies. Two additional papers also considered
people with type 1 diabetes: one in children reported that 6.6% had coeliac
disease (Salardi et al. 2008) and one in adults reported that 6.4% had coeliac
disease (Picarelli et al. 2005).
Other conditions
Papers were included that considered cohorts of people with specified other
conditions who were tested for coeliac disease (see table 2).
• autoimmune myocarditis
• chronic thrombocytopenic purpura
• depression/bipolar disorder
• Down’s syndrome
• The GDG agreed that there were certain signs and symptoms and
coexisting conditions (as well as the known risk factor of being a first-
degree relative of a person with coeliac disease) that are sufficiently
associated with coeliac disease that people with them should be offered
serological testing, and developed recommendations to reflect this. The
GDG discussed the historic division of symptoms into gastrointestinal and
non-gastrointestinal and concluded that it would be more beneficial to
identify the overall signs and symptoms for which testing would be
recommended. The GDG further discussed the non-specific nature of many
of the signs and symptoms and consequently added 'unexplained' and
'chronic' to the description of some signs and symptoms to ensure that
people who may have coeliac disease are identified.
• The GDG agreed a list of further signs, symptoms and coexisting
conditions for which they wanted to raise awareness of the link with coeliac
disease. Therefore recommendations were developed that identified where
offering serological testing for coeliac disease should be considered.
• The GDG discussed weight loss as a feature of coeliac disease and noted
that, although weight loss can be a symptom of coeliac disease, the
traditional view of a patient with coeliac disease being underweight is no
Recommendation 1.1.1
Offer serological testing for coeliac disease to children and adults with any of
the following signs and symptoms:
Recommendation 1.1.2
Offer serological testing for coeliac disease to children and adults with:
• Addison's disease
• amenorrhoea
• aphthous stomatitis (mouth ulcers)
• autoimmune liver conditions
• autoimmune myocarditis
• chronic thrombocytopenia purpura
• dental enamel defects
• depression or bipolar disorder
• Down’s syndrome
• epilepsy
• low-trauma fracture
• lymphoma
• metabolic bone disease (such as rickets or osteomalacia)
• microscopic colitis
• persistent or unexplained constipation
• persistently raised liver enzymes with unknown cause
• polyneuropathy
• recurrent miscarriage
• reduced bone mineral density
• sarcoidosis
• Sjögren's syndrome
• Turner syndrome
• unexplained alopecia
• unexplained subfertility.
Recommendation 1.1.4
Do not use serological testing for coeliac disease in infants before gluten has
been introduced to the diet.
• IgA AGA
• IgG AGA
• IgA EMA
• IgG EMA
• IgA tTGA
• IgG tTGA.
2
If studies used different cut-off levels, the data used were that of the manufacturer‘s
recommended cut-off levels.
IgA deficiency
People with IgA deficiency will have a false negative result if IgA-based
serological tests are used in the diagnosis of coeliac disease. It has been
suggested that there has been inadequate evaluation of IgA deficiency while
testing for coeliac disease, which has resulted in the underdiagnosis of both
(McGowan et al. 2008). Therefore, this guideline also considered the use of
IgA-deficiency testing and IgG-based serological testing in the diagnostic
process for coeliac disease.
Included studies
All studies considered people with suspected coeliac disease who had one of
the included serological tests and had coeliac disease confirmed by biopsy.
There were 29 studies included from the AHRQ (2004) report, 18 in children
The overall efficacy of the IgA AGA, IgA EMA and IgA tTGA serological tests
was summarised in forest plots and ROC curves (see appendix 6.3). The
ROC curves below show the overall results for the IgA AGA, tTGA and EMA
tests. They show a lower level of accuracy for the IgA AGA than the other
tests, with both IgA EMA and IgA tTGA identified as having high levels of both
sensitivity and specificity. For AGA the IgA serological tests results appeared
to show higher sensitivity and specificity than the IgG tests. For IgG tTGA and
IgG EMA there were insufficient data available to draw reasonable
conclusions.
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Sensitivity
A paper from the Czech Republic (Kocna et al. 2002) considered a two-step
screening algorithm and identified IgA/IgG AGA to be the least accurate
Three studies in the AHRQ report considered the use of IgA/IgG AGA
together or each individually; they did not find the combination results to be
notably different from the individual tests.
Age
ROC curve analysis categorising studies into those with child participants,
those with adult participants and those with mixed (child and adult)
participants reflected the overall analysis, with both IgA EMA and IgA tTGA
(there is insufficient evidence for IgG in either test to plot on the curves)
showing considerably higher levels of sensitivity and specificity than IgA or
IgG AGA.
One study (Viola 2004) also considered IgA AGA, IgA EMA and IgA tTGA
results in children 2 years and younger and those older than 2 years. It found
similar results in both age categories for IgA tTGA and for IgA EMA.
• Liver disease: one study of 105 participants who had primary biliary
cirrhosis reported a specificity range for IgA tTGA of 82.5 to 97.1% and
95.1 to 100% for IgG tTGA (Bizzaro et al. 2006). The authors noted that
with almost all the antibody concentrations IgA tTGA was close to the cut-
off level, and that positive results were inconsistent between the test kits.
They identified a concern about the false-positive rate with IgA tTGA testing
in people with primary biliary cirrhosis, although only six participants had
biopsies.
• IgA deficiency: one paper was identified that considered the use of IgG
AGA and IgG tTGA tests in 126 children with IgA deficiency (Lenhardt et al.
2004). Eleven were diagnosed with coeliac disease: all were IgG tTGA
positive and five were also IgG AGA positive, this suggests that IgG tTGA
is more accurate than IgG AGA in children with IgA deficiency.
Newer tests
Deamidated gliadin
Two papers were included that considered the use of deamidated gliadin
peptide (DGP)-based assays as a diagnostic tool for coeliac disease. The first
paper considered the use of IgA and IgG antibodies to synthetic DGP and
tTGA in 176 children (Agardh et al. 2007) and found 119 (68%) with coeliac
disease.
The second study considered 141 adults and used IgA tTGA and IgA/IgG
DGP; 60 were diagnosed with coeliac disease (Niveloni et al. 2007).
Results for both of these studies using deamidated gliadin peptide showed
sensitivity and specificity values similar to those found with tTGA.
• IgA/G tTGA (tTG stick): children sensitivity 97%, specificity 98%; adults
sensitivity 83%, specificity 100%
• IgA tTGA (tTG-AGA stick): children sensitivity 96%, specificity 98%; adults
sensitivity 80%, specificity 100%
• IgA AGA (tTG-AGA stick): children sensitivity 89%, specificity 96%; adults
sensitivity 83%, specificity 100%
• IgA tTGA + AGA (stick, one test): children sensitivity 99%, specificity 95%;
adults sensitivity 86%, specificity 100%.
Based on limited clinical evidence, combination testing with IgA tTGA and IgA
EMA does not appear to substantially to improve accuracy in the diagnostic
process.
There is limited evidence that IgA tTGA yields more false positive results in
people with liver disease than in the general population.
Newer tests for deamidated gliadin may be useful but require further
evaluation.
3
Can be used for self-test or point of care testing.
None of the 10 papers examining the cost effectiveness of serological tests for
coeliac disease was considered directly applicable to this guideline. However,
one UK study (Dretzke et al. 2004) examined serological tests and used
quality-adjusted life-years (QALYs) as an outcome measure, so was reviewed
in detail for this guideline. The remaining papers were used to explore
previous approaches to modelling serological test strategies and to inform the
structure of the model but were not quality-assessed or reviewed in detail for
A full data extraction form for Dretzke et al. (2004) is available in appendix 6.5
and the techniques from that study (2004) have been examined alongside
careful consideration of the modelling methods used by the other studies
identified in the review.
• no screening
• biopsy of all children
• single autoantibody test confirmed by biopsy in those testing positive
• combination of autoantibody tests confirmed by biopsy in those testing
positive
• single autoantibody test without confirmatory biopsy
• combination of autoantibody tests without confirmatory biopsy.
The authors were clear that not all of these strategies are used in current
clinical practice, although all strategies were included for completeness. The
analysis took an NHS perspective, with costs and outcomes modelled over a
lifetime.
Costs were estimated for serological tests, endoscopy and biopsy, and gluten-
free diet. Personal communication was used to evaluate the costs of the
serological tests; this is likely to be because of the absence of a national tariff
for diagnostic tests (such as the British National Formulary for drug prices).
All strategies were compared with a no-screening strategy. The lowest cost
per QALY gained was for a positive IgA EMA with confirmatory biopsy, with an
incremental cost-effectiveness ratio of £12,250 per QALY gained compared
with no screening. The least cost-effective strategies were those using IgG
AGA tests alone or in combination with other autoantibody tests. The authors
reported that the results were sensitive to the disutility of being on a gluten-
free diet, the cost of gluten-free diet, the differences in utilities between health
states and the reduction in life expectancy as a result of coeliac disease.
Because of the lack of published economic evidence that fully addresses the
cost effectiveness of serological testing in the decision-making context of this
guideline, the GDG requested the development of a de novo model. Any cost-
effectiveness analysis carried out should also examine the costs and
consequences of the outcomes of diagnosis. Although it is outside the scope
of this guideline to make recommendations on the treatment or management
of coeliac disease, the economic evaluation considers the costs and benefits
of current standard practice after diagnosis of coeliac disease. This allows us
to include the long-term consequences of testing, along with the costs and
consequences of incorrect diagnosis.
Serological tests examined in the model were the IgA tTGA and the IgA EMA
tests. These were analysed alone and in combination. In all cases, tests were
followed by biopsy to confirm positive results. Strategies with separate IgA
deficiency testing were also included. For completeness a no-test strategy
and a biopsy-only strategy were included.
The clinical systematic review identified several studies on the sensitivity and
specificity of serological tests for coeliac disease. There was no evidence
synthesis for these studies, for reasons explained in appendix 6.4. Therefore
data on sensitivity and specificity were taken from a UK-based, good quality
study (Hopper et al. 2008). This evaluated the sensitivity and specificity of
several serological test strategies in 2000 patients who had been referred for
biopsy. The results of the study were confirmed by biopsy. This study was
considered to provide the best available evidence on diagnostic accuracy to
inform the base-case economic model.
The model included the following costs: serological tests, endoscopy and
biopsy, gluten-free diet and follow-up to the NHS, and delayed diagnosis.
Costs were based on national-level costs from published sources, calculations
and data provided by laboratories. Costs were considered from an NHS and
personal social services (PSS) perspective as stated in the guideline scope.
The cost of serological testing is difficult to estimate because there is no
national tariff available. Cost of serological tests can vary greatly depending
on who orders the tests and how they are carried out. Economies of scale are
also realised when using diagnostic equipment, so the cost may differ
depending on the volume of tests carried out by the laboratory. For the
present analysis, the costs of serological tests have been estimated from data
provided by two laboratories in the UK following communication with a GDG
member. It is important to note that the methods laboratories use when
charging for serological tests means that the cost of two tests or combination
testing is often only marginally more expensive than a single test. This is
because most laboratories charge a fixed fee for coeliac disease testing,
based on an average of all tests for coeliac disease including the cost for
tTGA plus any additional tests needed.
Full details of the model, including results and sensitivity analysis, are
presented in appendix 6.5.
The model suggests that the no-test strategy is both the least effective
strategy (that is, produces the least number of QALYs) and the least costly
Because all the testing strategies have similar sensitivity and specificity, the
incremental differences in QALYs between them are very small. However, the
biopsy-only strategy is the most expensive, costing about £380 more than the
next most expensive strategy. Therefore, although a biopsy-only strategy may
be preferable to a no-test strategy those strategies that include serological
tests before confirmatory biopsy for positive results are still more cost effective
than the biopsy-only strategy
Combinations of EMA and tTGA tests had sensitivity and specificity similar to
the individual test strategies. The method of costing the test strategies did not
significantly affect the results. Therefore carrying out any of the test strategies
remains cost effective compared to no testing. Sensitivity analysis was carried
out to evaluate the effect of charging separately for these tests at high cost.
Even when additive fees are considered, the cost effectiveness is still similar
between the strategies because the costs of the tests are relatively low
compared with the cost and disutility of undiagnosed coeliac disease.
Probabilistic sensitivity analysis was also carried out. Distributions were added
to the sensitivity and specificity of each of the test strategies, the prevalence
of coeliac disease in the population of interest and the cost of delayed
diagnosis. At a threshold of £20,000 per QALY gained (the lower end of the
threshold considered acceptable by NICE), the probability of the test
strategies being cost effective was 100%. At around £6000 per QALY gained,
the probability of each of the strategies becoming cost effective approached
100%.
Full details of the model including results, and all sensitivity analyses, are
presented in appendix 6.5.
Recommendation 1.1.5
Inform people (and their parents or carers, as appropriate) that any testing
for coeliac disease is accurate only if the person continues to follow a
gluten-containing diet during the diagnostic process (serological tests and
biopsy if required).
Recommendation 1.1.7
Inform people that when they are following a normal diet (containing gluten)
they should eat some gluten (for example, bread, chapattis, pasta, biscuits,
or cakes) in more than one meal every day for a minimum of 6 weeks
before testing; however, it is not possible to say exactly how much gluten
they should eat.
Recommendation 1.1.8
If a person is reluctant or unable to reintroduce gluten into their diet before
testing:
Recommendation 1.1.9
Inform people who are considering, or have undertaken, self-testing for
coeliac disease (and their parents or carers) that any result from self-
testing needs to be discussed with a healthcare professional and confirmed
by laboratory-based tests.
Recommendation 1.1.11
Inform people and their parents or carers that a delayed diagnosis of
coeliac disease, or undiagnosed coeliac disease, can result in:
Recommendation 1.1.12
All tests should be undertaken in laboratories with clinical pathology
accreditation (CPA).
Recommendation 1.1.13
Do not use immunoglobulin G (IgG) or immunoglobulin A (IgA) anti-gliadin
antibody (AGA) tests in the diagnosis of coeliac disease.
Recommendation 1.1.14
Do not use of self-tests and/or point-of-care tests for coeliac disease as a
substitute for laboratory-based testing.
Recommendation 1.1.16
Do not use human leukocyte antigen (HLA) DQ2/DQ8 testing in the initial
diagnosis of coeliac disease. (However, its high negative predictive value
may be of use to gastrointestinal specialists in specific clinical situations.)
Recommendation 1.1.17
Offer referral to a gastrointestinal specialist for intestinal biopsy to confirm
or exclude coeliac disease to people with positive serological results from
any tTGA or EMA test.
Recommendation 1.1.18
If serology tests are negative but coeliac disease is still clinically suspected,
offer referral to a gastrointestinal specialist for further assessment.
4
Investigation for IgA deficiency should be done when the laboratory detects a low optical
density (OD) on IgA tTGA test, very low IgA tTGA results or low background on IgA EMA test.
3.1 References
Abrams JA, Brar P, Diamond B, et al. (2006) Utility in clinical practice of
immunoglobulin A anti-tissue transglutaminase antibody for the diagnosis of
celiac disease. Clinical Gastroenterology and Hepatology 4: 726–30
Bingley PJ, Williams AJK, Norcross AJ, et al. (2004) Undiagnosed coeliac
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Case–control study
Comparative observational study in which the investigator selects people who
have experienced an event (for example, developed a disease) and others
who have not (controls), and then collects data to determine previous
exposure to a possible cause.
Cohort study
An observational study in which a defined group of people (the cohort) is
followed over time. Outcomes are compared in subsets of the cohort who
were exposed or not exposed (or exposed at different levels) to an
intervention or other factor of interest.
Confidence interval
The range within which the ‘true' values (for example, size of effect of an
intervention) are expected to lie with a given degree of certainty (for example,
95% or 99%). (Note: confidence intervals represent the probability of random
errors, but not systematic errors or bias).
Cost-effectiveness analysis
An economic evaluation that compares alternative options for a specific
patient group, looking at a single effectiveness dimension measured in a non-
monetary (natural) unit. It expresses the result in the form of an incremental
(or average or marginal) cost-effectiveness ratio.
Cost–utility analysis
An economic evaluation that compares alternative options for a specific
patient group, looking at a single effectiveness dimension measured in a non-
monetary (natural) unit that also takes quality of life into account. It expresses
the result in the form of incremental cost per quality-adjusted life year (QALY)
gained.
False negative
A negative result in a diagnostic test when the person being tested does
possess the attribute for which the test is conducted.
False positive
A positive result in a diagnostic result when the person being tested does not
possess the attribute for which the test is conducted.
Generalisability
The degree to which the results of a study or systematic review can be
extrapolated to other circumstances.
Heterogeneity
A term used to illustrate the variability or differences among studies. High
heterogeneity indicates greater differences.
Odds ratio
A measure of treatment effectiveness. The likelihood of an event happening in
the intervention group, divided by the likelihood of it happening in the control
group. The ‘odds ratio’ is the ratio of non-events to events.
Reference standard
An agreed standard, for example for a test or treatment, against which other
interventions can be compared.
Relative risk
Also known as risk ratio; the ratio of risk in the intervention group to the risk in
the control group. The risk (proportion, probability or rate) is the ratio of people
with an event in a group to the total number of people in the group. A relative
risk (RR) of 1 indicates no difference between the groups being compared.
True negative
A negative result in a diagnostic test, when the person does not possess the
attribute for which the test is conducted.
True positive
A positive result in a diagnostic test, when the person does possess the
attribute for which the test is conducted.
Utility
A measure of the strength of a person's preference for a specific health state
in relation to alternative health states. The utility scale assigns numerical
values on a scale of 0 (death) to 1 (optimal or 'perfect' health). Health states
can be considered worse than death and thus have a negative value.
Estimates of utility – ideally based on the use of standardised and validated
3.3 Abbreviations
AGA Anti-gliadin antibodies
CI Confidence interval
EMA Anti-endomysial antibodies
IgA Immunoglobulin A
IgG Immunoglobulin G
NPV Negative predictive value
OR Odds ratio
PPV Positive predictive value
QALY Quality-adjusted life year
RCT Randomised controlled trial
RR Relative risk
SD Standard deviation
tTGA Anti tissue transglutaminase antibodies
4 Methods
4.1.1 Scope
NICE guidelines are developed in accordance with a scope that defines what
the guideline will and will not cover (see appendix 1). The scope of this
guideline is available from www.nice.org.uk/CG86
The search strategies for the key clinical questions were developed by the
Information Services Team with advice from the Short Clinical Guidelines
Technical Team. Structured clinical questions were developed using the PICO
(population, intervention, comparison, outcome) model and were translated
into search strategies using subject heading and free text terms. The
strategies were run across a number of databases with no date restrictions
imposed on the searches.
The searches were undertaken between May and October 2008. Full details
of the systematic search, including the sources searched and the MEDLINE
strategies for each evidence review, are presented in appendix 6.4.
The papers chosen for inclusion were then critically appraised by the Short
Clinical Guidelines Technical Team for their methodological rigour against a
number of criteria that determine the validity of the results. These criteria
differed according to study type, and the level of evidence ascribed to them
was based on the checklists included in ‘The guidelines manual’ (2009).
The data were extracted to standard evidence table templates. The findings
were summarised by the Short Clinical Guidelines Technical Team into both a
series of evidence statements and an accompanying narrative summary.
4.2.10 Consultation
The draft of the full guideline was available on the website for consultation
from 15 January to 12 February 2009, and registered stakeholders were
informed by NICE that the documents were available. Non-registered
stakeholders could view the guideline on the NICE website.
This guideline will be considered for an update following the current process
(chapter 14 of ‘The guidelines manual’ [2009]).
5 Contributors
Adrian Thomas
Consultant Paediatric Gastroenterologist
Alison Lister
Patient/carer member
David Sanders
Consultant Gastroenterologist
Julian Walters
Consultant Gastroenterologist
Mohamed Abuzakouk
Consultant Immunologist
Norma McGough
Patient/carer member
Peter Macfarlane
Consultant Paediatrician
Sorrel Burden
Dietitian
Tim Stokes
Associate Director, Centre for Clinical Practice
Beth Shaw
Technical Adviser
Roberta Richey
Technical Analyst
Michael Heath
Project Manager
Daniel Tuvey
Information Specialist
Nicole Elliott
Guidelines Commissioning Manager
Emma Banks
Guidelines Coordinator
Dr Graham Archard
General Practitioner, Dorset
Ms Karen Cowley
Practice Development Nurse, York
Dr David Gillen
Medical Director, Wyeth Pharmaceutical
Ms Catherine Arkley
Lay member
BUPA
Cheshire PCT
Coeliac UK
Department of Health
DHSSPSNI
Glutafin
Leeds PCT
NCCHTA
NHS Bedfordshire
NHS Kirklees
NHS Knowsley
NHS Plus
NHS Sefton
NHS Sheffield
SACAR
Sedgefield PCT
Sheffield PCT
Shire Plc
Teva UK Limited
University of Oxford
Wellfoods Ltd